HIV-1, reactive oxygen species, and vascular complications

Abstract

Over 1 million people in the United States and 33 million individuals worldwide suffer from HIV/AIDS. Since its discovery, HIV/AIDS has been associated with an increased susceptibility to opportunistic infection due to immune dysfunction. Highly active antiretroviral therapies (HAART) restore immune function and, as a result, people infected with HIV-1 are living longer. This improved survival of HIV-1 patients has revealed a previously unrecognized risk of developing vascular complications, such as atherosclerosis and pulmonary hypertension. The mechanisms underlying these HIV-associated vascular disorders are poorly understood. However, HIV-induced elevations in reactive oxygen species, including superoxide and hydrogen peroxide, may contribute to vascular disease development and progression by altering cell function and redox-sensitive signaling pathways. In this review, we summarize the clinical and experimental evidence demonstrating HIV- and HIV antiretroviral therapy-induced alterations in reactive oxygen species (ROS) and how these effects likely contribute to vascular dysfunction and disease.

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

“…Likewise, we now document involvement of ROS in cocaine-and Tat-mediated ligandindependent activation of PDGFRb at Y934. HIV-1 proteins are known to induce oxidative stress, thereby disrupting the balance of oxidants/antioxidants in favor of pathogenesis (32). Similar to our earlier reports of enhanced levels of ROS in pulmonary endothelial cells on exposure to viral proteins and/or opioids (11, 45), we found an additive increase in the generation of ROS in HPASMCs treated with cocaine and Tat compared with monotreatments.…”

Microvascular Endothelial Dysfunction and Enhanced Thromboxane and Endothelial Contractility in Patients with HIV

“…HIV leads to systemic oxidative stress from three sources: HIV infection, shed HIV-related proteins, and HAART [12]. Indirect, brachial artery endothelial-dependent flow-mediated dilation studies concluded that patients with HIV had impaired [10] or intact [35] endothelial function associated with protease inhibitors [11], or independent of HAART [10].…”

“…However, conduit artery function [14] does not predict microvascular dysfunction consistently [13,36]. HAART [37] and HIV-1 proteins [12] both caused endothelial dysfunction and oxidative stress in cells or animals. Thus, the enhanced microvascular ROS and endothelial dysfunction in the patients were likely the outcome of prolonged HIV infection and circulating HIV proteins [12], complicated by vascular inflammation and HAART [11].…”

“…Subjects with HIV infection have vascular inflammation [9] and endothelial dysfunction as assessed indirectly from brachial artery flow-mediated vasodilatation (FMD) [10]. This has been related in some [11], but not all [10] studies, to HAART or to increased systemic markers of reactive oxygen species (ROS) [12]. …”

Exercise and Atherosclerotic Cardiovascular Disease

“…An early event in atherogenesis is the activation of ECs in response to the injurious effects of glycated or oxidized LDL, oscillatory or diminished levels of shear stress, infection with agents such as CMV, HIV-1, or Chlamydia pneumoniae, free radicals arising during oxidative stress, heat shock protein 60, hypertension, cigarette smoking and/or inactivity [10,16,[29][30][31][32][33][34][35]. Activated ECs upregulate their production of chemokines, adhesins, VSMC growth and activation factors, and downregulate their production of TGF-β, vasodilators, antioxidants, and anticoagulants.…”